ABSTRACT We have assembled a multidisciplinary team of investigators to investigate how the brain and key peripheral metabolic signals regulate feeding and glucose homeostasis following exercise. In particular, we have developed a program focused on using unique, genetic mouse models to understand why exercise training improves multiple metabolic parameters including insulin sensitivity and changes in body composition. We propose a set of projects that revolve around the hypothesis that several of these exercise-associated effects are mediated by changes in key brain circuits. The investigators involved in this application, Elmquist, Betley Zigman, and Williams bring distinct and synergistic expertise to the table. The Elmquist/Betley group will investigate the role of the ventromedial hypothalamus nucleus (VMH) neurons in the regulation of metabolic changes induced by exercise. The Zigman group will investigate the physiological importance of ghrelin signaling in regulating responses to exercise. The Williams group will investigate the changes in fundamental cellular properties of hypothalamic neurons following exercise training These three tightly interwoven Projects will address a number of new aspects of inter-organ communication between the peripheral tissues and critical regions in the brain. Three Cores will support the three Projects in these efforts: A) Administrative Core; B) Mouse Exercise and Metabolic Phenotyping Core and the C) Neuroanatomy/Histology/Brain Injection Core. In summary, these innovative and synergistic studies will increase the understanding of how exercise training regulates key peripheral metabolic signals via changes in central nervous system circuits.